1. Field of the Invention
This is a method of treatment of cardiac arrhythmias and repolarization abnormalities associated with long QT syndrome (LQTS) and/or congestive heart failure (CHF). This method is also useful in ameliorating or improving contractile dysfunction in CHF by hastening cardiac repolarization and relaxation and/or increasing the diastolic filling time and thereby reducing the workload of the failing heart, reducing oxygen consumption and improving cardiac performance. The method utilizes a compound that acts to enhance or activate cardiac potassium (K.sup.+) channels and shorten the cardiac action potential (AP), thereby hastening repolarization, decreasing systolic contraction time and prolonging the diastolic filling time. Specific examples of compounds that act to enhance the slowly activating cardiac delayed rectifier potassium current (I.sub.Ks) are presented. This effect of increasing the repolarizing K.sup.+ current, I.sub.Ks, causes a shortening of action potential duration (APD) that occurs as a consequence of a direct action of the compound on slowly activating cardiac delayed rectifier potassium channels in the cardiac plasma membrane underlying I.sub.Ks, and not through an effect on other indirect pathways, such as, binding and stimulation of .beta.-adrenergic receptors. The shortening of APD acts to prevent or reverse the electrophysiologic and contractile abnormalities that occur in LQTS and CHF, including delayed repolarization, ventricular arrhythmias, and delayed relaxation of the myocardium which compromises contractility and the pumping efficiency of the heart.
2. Description of Related Art
Cardiac arrhythmias often occur as a complication of cardiac diseases such as myocardial infarction and heart failure. Certain cardiac arrhythymias result from electrolyte imbalances, dietary deficiencies, exposure to drugs, or congenital abnormalities (Jackman W N, Friday K J, Anderson J L, Aliot E M, Clark M and Lazzara R. (1988). The Long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 31: 115-172.), which produce changes in the density or regulation of various ion channels and cause abnormally long APs. In particular, aberrant cardiac repolarization, whereby APs become excessively long, predisposes patients to the risk of dangerous cardiac arrhythmias and sudden cardiac death (SCD), and is well known to occur in various acquired and genetic forms of LQTS (Roden D M, Lazzara R, Rosen M, Schwartz P J, Towbin J and Vincent G M. (1996). Multiple mechanisms in the Long-QT Syndrome; Current knowledge, gaps and future directions. Circulation 94: 1996-2012.), and in CHF (Tomaselli G F, Beuckelmann D J, Calkins H G, Berger R D, Kessler P D, Lawrence J H, Kass D, Feldman A M and Marban E. (1994). Suden cardiac death in heart failure. The role of abnormal repolarization. Circulation 90: 2534-2539.). In myocardial cells there is an ensemble of inward and outward currents that results from the flow of various inorganic ions through the cell membrane. These currents are due to the presence of selective cation and anion channels in the plasma membrane. The voltage- and time-dependent opening (activation) and closing (inactivation and/or deactivation) of these ion channels in cardiomyocytes result in the characteristically long cardiac APs (depolarization with delayed repolarization). After an initial rapid upstroke or depolarization, there is a plateau of maintained depolarization followed by repolarization to the resting membrane potential. Thus, APD is primarily responsible for the time-course of repolarization of the heart; prolongation of APD produces delays in cardiac repolarization, often manifest as an increase in the electrocardiographic QT interval. Cardiac APs also underlie a coordinated conduction of electrical impulses throughout the heart, trigger the synchronized contraction of the heart and, to some extent, control the force of the contraction. If these APs develop abnormal configuations and/or automaticity or become unsynchronized, then fatal cardiac arrhythmias can occur. As a rule, the longer the APD, the more labile is the cardiac repolarization process. This lability may be exhibited as pronounced variability or excessive prolongation in APD that can initiate or trigger early after-depolarizations (EAD) in cardiac myocytes, in vitro, which is one mechanism for induction of ventricular arrhythmias (Brugada P and Wellens H J J. (1985). Early afterdepolarizations: role in conduction block, prolonged repolarization-dependent re-excitation, and tachyarrhythmias in the human heart. PACE 8: 889-896; January C T and Fozzard H A. (1988). Delayed afterdepolarizations in heart muscle: Mechanisms and relevance. Pharmacol Rev 40: 219-227; January C T and Moscucci A. (1992). Cellular mechanisms of early afterdepolarizations. Annal NY Acad Sci 644: 23-32.).
Repolarization from the plateau phase of the AP in ventricular myocytes is controlled by a delicate balance between inward and outward currents in the setting of a high membrane resistance. Prolongation of APD can occur as a consequence of decreases in outward currents or increases in inward currents. Important outward currents that determine repolarization are the rapidly (I.sub.Kr) and slowly (I.sub.Ks) activating delayed rectifier K.sup.+ currents (Sanguinetti M C and Jurkiewicz N K. (1990). Two components of cardiac delayed rectifier K.sup.+ current: Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 96: 195-215.). Several class III antiarrhythmic agents selectively block I.sub.Kr, and thereby prolong APD and the QT interval on the electrocardiogram. Excessive APD prolongation by these drugs causes acquired long QT syndrome (LQTS) that is associated with torsades de pointes, a ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and cause SCD.
LQTS can also be inherited. The finding that mutations in HERG, the gene that encodes I.sub.Kr channels cause inherited LQTS (Curran M E, Splawski I, Timothy K W, Vincent G M, Green E D and Keating M T. (1995). A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80: 795-804.; Sanguinetti M C, Curran M E, Spector P S and Keating M T. (1996a). Spectrum of HERG K.sup.+ channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci USA 93: 2208-2212.; Sanguinetti M C, Jiang C, Curran M E and Keating M T. (1995). A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the I.sub.Kr potassium channel. Cell 81: 299-307.) provided a mechanistic link between acquired LQTS and one form of inherited LQTS. The most common form of LQTS is caused by mutations in KvLQT1, a novel K.sup.+ channel gene (Wang Q, Curran M E, Splawski I, Burn T C, Millholland J M, VanRaay T J, Shen J, Timothy K W, Vincent G M, de Jager T, Schwartz P J, Towbin J A, Moss A J, Atkinson D L, Landes G M, Connors T D and Keating M T. (1996). Positional cloning of a novel potassium channel gene: KvLQT1 mutations cause cardiac arrhythmias. Nature Genetics 12: 17-23.). Expression of KvLQT1 in either Xenopus oocytes or mammalian cell lines induced a K.sup.+ current with biophysical properties unlike any known cardiac K.sup.+ current. Co-expression of KvLQT1 with minK induced a current that was essentially identical to cardiac I.sub.Ks, indicating that KvLQT1 and minK proteins co-assemble to form I.sub.Ks channels (Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M and Romey G. (1996). KvLQT1 and I.sub.sK (minK) proteins associate to form the I.sub.Ks cardiac potassium current. Nature 384: 78-80.; Sanguinetti M C, Curran M E, Zou A, Shen J, Spector P S, Atkinson D L and Keating M T. (1996b). Coassembly of KvLQT1 and minK (I.sub.sK) proteins form cardiac I.sub.Ks potassium channel. Nature 384: 80-83.). Thus, dysfunction of either I.sub.Kr or I.sub.Ks can increase the risk of cardiac arrhythmia and SCD.
CHF is a common, highly lethal cardiovascular disorder that affects over 2 million people and claims over 200,000 lives a year in the U.S. It is estimated that .gtoreq.50% of deaths in CHF patients are sudden and that the majority of these are most likely the result of ventricular tachycardia. Myocytes isolated from failing animal and human hearts consistently exhibit a significant prolongation of APD compared with those of normal hearts, independent of the mechanism of CHF (Tomaselli, et al. (1994). Sudden cardiac death in heart failure. The role of abnormal repolarization. Circulation 90: 2534-2539.). The increase in APD in animal models and human CHF do not appear to occur as a result of alterations of the inward currents, I.sub.Na and I.sub.Ca, but decreases in at least two voltage-dependent outward K.sup.+ currents have been consistenly observed. Both the transient outward current, I.sub.to, and the inward rectifier K.sup.+ current, I.sub.K1, have been shown to be reduced in heart failure. Recent studies have also shown that I.sub.Ks is decreased in animal models of heart failure and human CHF (Li G R, Sun H, Nattel, S (1998). Action potential and ionic remodelling in a dog model of heart failure. PACE 21:877; Li G R, Sun H, Feng J, Nattel, S (1998). Ionic mechanisms of th action potental prolongation in failing human ventricular cells PACE 21:877). Reductions in these outward K+currents are consistent with a prolongation of APD because they act to repolarize cardiac cells. Reductions in the rapid (I.sub.Kr) component of the delayed rectifier K.sup.+ currents could also result in an increase in APD, but effects on this current in CHF remain to be determined.
In CHF reductions in outward currents during the plateau phase of the cardiac AP lead to extraordinary increases in APD predisposing the heart to ventricular arrhythmias, much like the electrophysiological changes in LQTS. For example, AP recorded from isolated ventricular myocytes obtained from human failing myocardium were very prolonged compared to those from normal hearts (Beuckelmann I) J, Nabauer M and Erdmann E. (1993). Alterations of K.sup.+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res 73: 379-385.). This increase in APD was explained, at least partly by a decrease in I.sub.to as well as decreases in I.sub.K1 and I.sub.Ks (Nabauer M, Beuckelmann D J and Erdmann E. (1993). Characteristics of transient outward current in human ventricular myocytes from patients with terminal heart failure. Circ. Res. 73: 386-394.); Li G R, Sun H, Feng J, Nattel, S (1998). Ionic mechanisms of th action potental prolongation in failing human ventricular cells PACE 21:877). Likewise, in canine (Kaab S, Nuss B, Chiamvimonvat N, O'Rourke B, Pak P H, Kass D A, Marban E and Tomaselli G F. (1996). Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res 78: 262-273; Li G R, Sun H, Nattel, S (1998). Action potential and ionic remodelling in a dog model of heart failure. PACE 21:877) and rabbit (Rozanski G J, Xu Z, Whitney R T, Murakami H and Zucker I H. (1997). Electrophysiology of rabbit ventricular myocytes following sustained rapid ventricular pacing. J Mol Cell Cardiol 29: 721-732.) models of pacing induced-heart failure, APD of failing myocytes was statisically greater than normal controls. Similar effects on APD were evident in a renovascular hypertension-induced model of cardiac hypertrophy (Rials S J, Wu Y, Xu R A, Filart R A, Marinchak R A and Kowey P R. (1997). Regression of left ventricular hypertrophy with captopril restores normal ventricular action potetial duration, dispersion of refractoriness, and vulnerability to inducible ventricular fibrillation. Circulation 96: 1330-1336.).
Therefore, the disease states LQTS and CHF, exhibit rather similar electrophysiological abnormalities, that will be similarly responsive to pharmacological treatment. An agent or intervention that produces a decrease in APD, by causing opposing changes in the currents that underlie the increases in APD will produce a shortening of APD and thereby correct or prevent the electrophysiological abnormalities in LQTS and CHF. Pharmacological agents or other interventions that lead to an increase in outward current or a decrease in inward current will oppose prolongation of APD and therefore will be effective against arrhythmias in LQTS and CHF caused by excessive APD prolongation. For example, an activator of I.sub.Kr or I.sub.Ks channels will be useful for the treatment of LQTS that results from excessive pharmacological block of these channels, or from mutations in the genes that encode the channel proteins.